CN112316112A - 阿奇霉素在逆转食品动物源致病菌抗生素耐药性的用途 - Google Patents
阿奇霉素在逆转食品动物源致病菌抗生素耐药性的用途 Download PDFInfo
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- CN112316112A CN112316112A CN202011379551.5A CN202011379551A CN112316112A CN 112316112 A CN112316112 A CN 112316112A CN 202011379551 A CN202011379551 A CN 202011379551A CN 112316112 A CN112316112 A CN 112316112A
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- azithromycin
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- pathogenic bacteria
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
本发明涉及微生物耐药性技术领域,具体公开了阿奇霉素在逆转食品动物源致病菌抗生素耐药性的用途,所述抗生素为多黏菌素类抗生素。本发明首次发现了阿奇霉素能够逆转动物源致病菌对黏菌素耐药性,提供了新的用药策略,具有重要的新制剂研发和临床应用价值。
Description
技术领域
本发明涉及微生物耐药性技术领域,具体涉及阿奇霉素在逆转食品动物源致病菌抗生素耐药性的用途。
背景技术
多黏菌素(polymyxin)是由多黏类芽孢杆菌(Paenibacillus polymyxa)产生的一组多肽类抗生素,包括多黏菌素A、B、C、D、E等多种成分。多黏菌素E又名黏菌素(Colistin,简称COL),与多黏菌素B是人医临床、兽医临床上常用的两种阳离子多肽类抗菌药物。其主要通过分子中的聚阳离子环与细菌细胞外膜上类脂A作用,置换外膜中的钙、镁等阳离子,破坏阴性菌带负电荷的外膜而降低细胞膜稳定性,使细胞内重要物质外流产生杀菌作用。近年来,因用于治疗革兰氏阴性菌感染的碳青霉烯类、头孢菌素类和氟喹诺酮类等抗菌药物的耐药性普遍提高,黏菌素作为治疗革兰氏阴性菌感染的最后手段被广泛应用,这使得耐黏菌素的细菌不断被检出,给畜牧业及人类健康带来了严重威胁。
目前已阐明的黏菌素耐药机制主要是染色体介导的两个双组分信号转导系统(two-component signal transduction system,TCS)PhoPQ及PmrAB和质粒介导的黏菌素耐药基因mcr-1~9,两种机制最终都导致细菌外膜上的脂多糖(LPS)的修饰,即通过外膜LPS的类脂A磷酸基团的糖化(Ara4N化)或乙醇胺化(pETN化)修饰,导致阳离子黏菌素与细菌外膜阴性LPS的亲和力降低,使细菌耐药。
阿奇霉素(azithromycin)为15元环大环内酯类抗生素,分子式为C38H72N2O12,其通过抑制细菌蛋白质的合成而发挥抗菌活性。抗菌谱广,包括革兰阳性菌、革兰阴性球菌、革兰阴性杆菌及厌氧菌。另外,已有研究发现阿奇霉素可作为细菌外排泵抑制剂而发挥作用,1μg/mL的阿奇霉素可以抑制铜绿假单胞菌外排泵MexAB-OprM的表达。
目前,针对黏菌素耐药菌的频繁出现,采取的积极对策是使用新的策略来使用现有的药物,黏菌素联合用药策略或方案被大量研究。黏菌素联用的药物有以下几种:细菌蛋白质或RNA合成抑制剂,如利奈唑胺、利福平及夫西地酸等;磺胺类:磺胺嘧啶;驱虫药:氯硝柳胺;β-内酰胺酶抑制剂:舒巴坦等。与阿奇霉素联用的药物有红霉素、头孢类及中草药等,关于阿奇霉素与黏菌素的联用对动物源致病菌对黏菌素耐药性作用具体研究尚未报道。
发明内容
为解决上述技术问题,本发明提供了阿奇霉素在逆转食品动物源致病菌抗生素耐药性的用途。
优选的,所述抗生素为多黏菌素类抗生素。
优选的,所述多黏菌素类抗生素为多黏菌素B或多黏菌素E的任意一种。
优选的,所述阿奇霉素为其药学上可接受的盐。
优选的,所述阿奇霉素为盐酸阿奇霉素、乳糖酸阿奇霉素和阿奇霉素或者三者的组合物。
优选的,所述阿奇霉素能够逆转多黏菌素类抗生素耐药性中,阿奇霉素与多黏菌素的用量比为2-8μg:32μg。
优选的,所述食品动物源致病菌为革兰氏阴性菌。
优选的,所述食品动物源致病菌为大肠杆菌、沙门菌、肺炎克雷伯菌、鲍曼不动杆菌、弯曲菌、变形杆菌、嗜血杆菌、巴氏杆菌、胸膜肺炎放线杆菌或者鸭里默氏菌。
与现有技术相比,本发明的有益效果在于:
1、本发明首次发现了阿奇霉素能够增强大肠杆菌对黏菌素的敏感性,甚至逆转黏菌素耐药菌株对黏菌素的耐药性,使耐药菌株的耐药性降到耐药折点以下。
2、本发明首次发现了阿奇霉素能够逆转动物源致病菌对黏菌素耐药性,提供了新的用药策略,具有重要的新制剂研发和临床应用价值。
3、本发明所述的新用途是指体外联合用药方案,当多黏菌素类抗生素与阿奇霉素组合且阿奇霉素在适度浓度范围内,多黏菌素类抗生素对致病菌的抗菌活性明显增强,甚至逆转黏菌素耐药菌的耐药性,此组合可降低抗菌药物的使用剂量,增强治疗效果,具有较大的临床应用价值。
具体实施方式
下面对本发明的具体实施方式进行详细描述,但应当理解本发明的保护范围并不受具体实施方式的限制。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例,都属于本发明保护的范围。本发明各实施例中所述实验方法,如无特殊说明,均为常规方法。
实施例1:
阿奇霉素逆转临床分离株大肠杆菌E57黏菌素耐药性的作用观察
(1)试验药物
阿奇霉素:含量97%,购于四川恒瑞通达有限公司。
硫酸黏菌素:效价≥23000u/mg,购于河北圣雪大成唐山制药有限公司。
阿奇霉素用30%无水乙醇和去离子水配制成初始浓度为1280μg/mL的储备液;硫酸黏菌素用去离子水配制成初始浓度为1280μg/mL的储备液,于-20℃保存。
(2)菌株
临床分离的黏菌素耐药株大肠杆菌E57,mcr-1阳性,经克隆及测序验证该菌株的抗药性由mcr-1基因介导,由河南农业大学药理实验室提供。
(3)培养基
LB肉汤培养基(批号:150415):北京奥博星生物技术有限责任公司,按照本品说明书配制1000mL,121℃高压灭菌15min后,放凉后4℃保存备用。
MHB肉汤培养基(批号:150430):北京奥博星生物技术有限责任公司,按照本品说明书配制1000mL,121℃高压灭菌15min后,放凉后4℃保存备用。
(4)仪器
高压蒸汽灭菌锅(上海申安医疗器械厂);
AB204-N型电子分析天平(梅特勒-托利仪器上海有限公司);
HZQ-R空气浴振荡器(北京六一仪器厂);
DH-600电热恒温培养箱(北京科伟永兴仪器有限公司);
DHG-9140A型真空干燥箱(上海精宏实验仪器有限公司);
SW-CJ-JC超净工作台(苏州安泰空气技术有限公司)。
(5)菌液制备
在经划线接种的麦康凯琼脂板上挑取单菌落,接种至5ml LB肉汤培养基,于37℃180rpm摇床中振荡培养,待细菌处于指数生长期后期,取该菌液至MHB肉汤培养基中,使菌液浓度稀释至105CFU/ml。在此菌悬液中加入一定剂量的阿奇霉素储备液,使其为所需浓度,备用。
(6)MIC的测定及判定
参照CLSI规定的操作方法,使用二倍微量肉汤稀释法分别测定黏菌素和阿奇霉素对受试菌株的最小抑菌浓度(MICs)。再测定亚抑菌浓度(sub-MIC)的阿奇霉素存在时黏菌素对菌株的MIC。以不含药物的MHB肉汤作为阴性对照;以含有菌液的MHB肉汤作为阳性对照。96孔反应板于37℃恒温箱培养16-20h。
药物MIC值为96孔反应板中浑浊孔的前一个澄清透明孔的药物浓度。试验作三次重复。
根据CLSI规定的折点,以黏菌素MIC≥4μg/mL为耐药范围。
实施例1实验结果如下:
试验测试mcr-1阳性大肠杆菌分离株E57对黏菌素和阿奇霉素的敏感性,进一步使用1/2MIC、1/4MIC及1/8MIC的阿奇霉素浓度与黏菌素联用,结果如表1所示。
表1阿奇霉素对大肠杆菌分离株E57耐药性影响
注:COL:黏菌素;AZI:阿奇霉素;1/2MIC AZI:阿奇霉素加入量为8μg/mL;1/4MICAZI:阿奇霉素加入量为4μg/mL;1/8MIC AZI:阿奇霉素加入量为2μg/mL。
由表1可知,黏菌素和阿奇霉素对大肠杆菌E57的最小抑菌浓度(MIC)分别为32μg/mL、16μg/mL。当使用1/2、1/4及1/8MIC的阿奇霉素浓度添加至分离株E57菌悬液中时,再测试其对黏菌素的敏感性,发现黏菌素的MIC分别变为1μg/mL、4μg/mL和8μg/mL,其中1/2的阿奇霉素MIC使黏菌素的增效效果强于1/4和1/8的阿奇霉素MIC的效果,使菌株由耐药变为敏感。这表明阿奇霉素可增强大肠杆菌对黏菌素的敏感性,并可使耐药逆转为敏感。
实施例2:
阿奇霉素逆转临床分离株大肠杆菌ED16黏菌素耐药性的作用
实验药物、培养基、仪器、菌液制备和MIC的测定及判定方式均与实施例1基本相同,区别在于:
所用菌株为大肠杆菌分离株ED16,mcr-1阴性,经全基因组二代测序证明其为染色体突变或表达量升高介导的黏菌素耐药株,由河南农业大学药理实验室提供。
实施例2实验结果如下:
表2阿奇霉素对大肠杆菌分离株ED16耐药性的影响
注:COL:黏菌素;AZI:阿奇霉素;1/2MIC AZI:阿奇霉素加入量为16μg/mL;1/4MICAZI:阿奇霉素加入量为8μg/mL;1/8MIC AZI:阿奇霉素加入量为4μg/mL。
由表2可知,黏菌素和阿奇霉素对大肠杆菌ED16的MIC分别为8、32μg/mL。使用黏菌素分别和1/2、1/4及1/8MIC的阿奇霉素联用时,黏菌素的MIC分别变为1/8、1/8和1/4μg/mL,其MIC下降了64或32倍,MIC值降至黏菌素耐药折点(小于或等于4μg/mL)以下,较大程度地增强了黏菌素的作用活性。以上结果表明阿奇霉素可以逆转黏菌素耐药株对黏菌素的耐药性,降低黏菌素耐药株对黏菌素的抗药性。
实施例3:
黏菌素与阿奇霉素的体外联合用药测试
试验药物、培养基、仪器和菌液制备与实施例1相同,区别在于:
实验菌株为大肠杆菌分离株ELX11,mcr-1阳性,经克隆及测序验证该菌株的抗药性由mcr-1基因介导,由河南农业大学药理实验室提供。
MIC及FIC指数测定:
MIC测定和判读同实施例1,黏菌素和阿奇霉素联合对大肠杆菌的FIC(Fractionalinhibitory concentration,部分抑菌浓度指数)指数测定,采用8×8棋盘法测定两药联合的体外抗菌活性。FIC=黏菌素联合用药时的MIC/黏菌素单独时的MIC+阿奇霉素联合时的MIC/阿奇霉素单独时的MIC,≤0.5:协同作用;0.5-1:相加作用;1-2:无关作用;>2:拮抗作用。
实施例3实验结果如下:
表3黏菌素与阿奇霉素联合用药的FIC值
注:COL,黏菌素;AZI,阿奇霉素。
由表3可知,黏菌素与阿奇霉素联合用药对革兰阴性菌大肠杆菌FIC指数为0.25,其小于0.5,这说明黏菌素与阿奇霉素的联合对大肠杆菌表现为协同作用。其中,该联合能够使黏菌素对大肠杆菌的MIC降至1μg/mL,使黏菌素的作用效果增强了8倍,同时逆转了大肠杆菌耐药菌的耐药性,使其表现为黏菌素敏感。
需要说明的是,本发明研究的阿奇霉素能够增强黏菌素的药效,降低其作用菌株的耐药性,增强菌株对黏菌素的敏感性,而黏菌素主要对革兰氏阴性菌有强大抗菌作用,敏感菌有绿脓杆菌、大肠杆菌、肠杆菌属、克雷伯氏菌属、沙门氏菌属、志贺氏菌属、弯曲菌、变形杆菌、嗜血杆菌、巴氏杆菌、胸膜肺炎放线杆菌、鸭里默氏菌、巴斯德氏菌和弧菌,因此,本发明中阿奇霉素能够增强上述菌株对黏菌素的敏感性,从而逆转菌株耐药性。
尽管已描述了本发明的优选实施例,但本领域内的技术人员一旦得知了基本创造性概念,则可对这些实施例作出另外的变更和修改。所以,所附权利要求意欲解释为包括优选实施例以及落入本发明范围的所有变更和修改。
显然,本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样,倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内,则本发明也意图包含这些改动和变型在内。
Claims (8)
1.阿奇霉素在逆转食品动物源致病菌抗生素耐药性的用途。
2.根据权利要求1所述的用途,其特征在于,所述抗生素为多黏菌素类抗生素。
3.根据权利要求2所述的用途,其特征在于,所述多黏菌素类抗生素为多黏菌素B或多黏菌素E的任意一种。
4.根据权利要求1所述的用途,其特征在于,所述阿奇霉素为其药学上可接受的盐。
5.根据权利要求4所述的用途,其特征在于,所述阿奇霉素为盐酸阿奇霉素、乳糖酸阿奇霉素、阿奇霉素或者三者的组合物。
6.根据权利要求1所述的用途,其特征在于,所述阿奇霉素能够逆转多黏菌素类抗生素耐药性中,阿奇霉素与多黏菌素的用量比为2-8μg:32μg。
7.根据权利要求1所述的用途,其特征在于,所述食品动物源致病菌为革兰氏阴性菌。
8.根据权利要求7所述的用途,其特征在于,所述食品动物源致病菌为大肠杆菌、沙门菌、肺炎克雷伯菌、鲍曼不动杆菌、弯曲菌、变形杆菌、嗜血杆菌、巴氏杆菌、胸膜肺炎放线杆菌或者鸭里默氏菌。
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